Julia Chu

BACKGROUND: Dilated cardiomyopathy is characterized by an increase in ventricular size and impairment of ventricular function. Most cases are believed to be sporadic, and familial dilated cardiomyopathy is usually considered to be a rare and distinct disorder. We studied the proportion of cases of idiopathic dilated cardiomyopathy that were familial in a large sequential series of patients whose first-degree relatives were investigated regardless of whether these relatives had cardiac symptoms. METHODS: We studied relatives of 59 index patients with idiopathic dilated cardiomyopathy of obtaining a family history and performing a physical examination, electrocardiography, and two-dimensional, M-mode, and Doppler echocardiography. A total of 315 relatives were examined. RESULTS: Eighteen relatives from 12 families were shown to have dilated cardiomyopathy. Thus, 12 of the 59 index patients (20.3 percent) had familial disease. There was no difference in age, sex, severity of disease, exposure to selected environmental factors, or electrocardiographic or echocardiographic features between the index patients with familial disease and those with nonfamilial disease. A noteworthy finding was that 22 of 240 healthy relatives (9.2 percent) with normal ejection fractions had increased left ventricular diameters during systole or diastole (or both), as compared with 2 of 112 healthy control subjects (1.8 percent) who were studied separately. CONCLUSIONS: Dilated cardiomyopathy was found to be familial in at least one in five of the patients in this study, a considerably higher percentage than in previous reports. This finding has important implications for family screening and provides direction for further investigation into the causes and natural history of dilated cardiomyopathy.

Mesenchymal stem cells (MSCs) are a potential source for the construction of tissue-engineered vascular grafts. However, how vascular mechanical forces regulate the genetic reprogramming in MSCs is not well understood. Mechanical strain in the vascular wall is anisotropic and mainly in the circumferential direction. We have shown that cyclic uniaxial strain on elastic substrates causes the cells to align perpendicularly to the strain axis, which is different from that in the vascular wall. To simulate the vascular cell alignment and investigate the anisotropic mechanical sensing by MSCs, we used soft lithography to create elastomeric membranes with parallel microgrooves. This topographic pattern kept MSCs aligned parallel to the strain axis, and the cells were subjected to 5% cyclic uniaxial strain (1 Hz) for 2-4 days. DNA microarray analysis revealed global gene expression changes, including an increase in the smooth muscle marker calponin 1, decreases in cartilage matrix markers, and alterations in cell signaling (e.g., down-regulation of the Jagged1 signaling pathway). In addition, uniaxial strain increased MSC proliferation. However, when micropatterning was used to align cells perpendicularly to the axis of mechanical strain, the changes of some genes were diminished, and MSC proliferation was not affected. This study suggests that mechanical strain plays an important role in MSC differentiation and proliferation, and that the effects of mechanotransduction depend on the orientation of cells with respect to the strain axis. The differential cellular responses to the anisotropic mechanical environment have important implications in cardiovascular development, tissue remodeling, and tissue engineering.

Bone marrow mesenchymal stem cells (MSCs) can differentiate into a variety of cell types, including vascular smooth muscle cells (SMCs), and have tremendous potential as a cell source for cardiovascular regeneration. We postulate that specific vascular environmental factors will promote MSC differentiation into SMCs. However, the effects of the vascular mechanical environment on MSCs have not been characterized. Here we show that mechanical strain regulated the expression of SMC markers in MSCs. Cyclic equiaxial strain downregulated SM alpha-actin and SM-22alpha in MSCs on collagen- or elastin-coated membranes after 1 day, and decreased alpha-actin in stress fibers. In contrast, cyclic uniaxial strain transiently increased the expression of SM alpha-actin and SM-22alpha after 1 day, which subsequently returned to basal levels after the cells aligned in the direction perpendicular to the strain direction. In addition, uniaxial but not equiaxial strain induced a transient increase of collagen I expression. DNA microarray experiments showed that uniaxial strain increased SMC markers and regulated the expression of matrix molecules without significantly changing the expression of the differentiation markers (e.g., alkaline phosphatase and collagen II) of other cell types. Our results suggest that uniaxial strain, which better mimics the type of mechanical strain experienced by SMCs, may promote MSC differentiation into SMCs if cell orientation can be controlled. This study demonstrates the differential effects of equiaxial and uniaxial strain, advances our understanding of the mechanical regulation of stem cells, and provides a rational basis for engineering MSCs for vascular tissue engineering and regeneration.